Allergic disease is a common health problem affecting humans and companion animals (mainly dogs and cats) alike. Allergies exist to foods, molds, grasses, trees, insects, pets, fleas, ticks and other substances present in the environment. It is estimated that up to 8% of young children and 2% of adults have allergic reactions just to foods alone. Some allergic reactions (especially those to foods and insects) can be so severe as to be life threatening. Problems in animals tend to be less severe, but very common. For example, many dogs and cats have allergies to flea saliva proteins, grasses, and other common substances present in the environment.
Allergy is manifested by the release of histamines and other mediators of inflammation by mast cells which are triggered into action when IgE antibodies bound to their receptors on the mast cell surface are cross linked by antigen. Other than avoidance, and drugs (e.g., antihistamines, decongestants, and steroids) that only treat symptoms and can have unfortunate side effects and often only provide temporary relief, the only currently medically accepted treatment for allergies is immunotherapy. Immunotherapy involves the repeated injection of allergen extracts, over a period of years, to desensitize a patient to the allergen. Unfortunately, traditional immunotherapy is time consuming, usually involving years of treatment, and often fails to achieve its goal of desensitizing the patient to the allergen. Furthermore, it is not the recommended treatment for food allergies, such as peanut allergies, due to the risk of anaphylaxis.
Noon (Noon, Lancet 1911; 1:1572-73) first introduced allergen injection immunotherapy in 1911, a practice based primarily on empiricism with non-standardized extracts of variable quality. More recently the introduction of standardized extracts has made it possible to increase the efficacy of immunotherapy, and double-blind placebo-controlled trials have demonstrated the efficacy of this form of therapy in allergic rhinitis, asthma and bee-sting hypersensitivity (BSAC Working Party, Clin. Exp. Allergy 1993; 23:1-44). However, increased risk of anaphylactic reactions has accompanied this increased efficacy. For example, initial trials of immunotherapy to food allergens has demonstrated an unacceptable safety: efficacy ratio (Oppenheimer et al. J. Allergy Clin. Immun. 1992; 90:256-62; Sampson, J. Allergy Clin. Immun. 1992; 90:151-52; Nelson et al. J. Allergy Clin. Immun. 1996; 99:744-751). Results like these have prompted investigators to seek alternative forms of immunotherapy as well as to seek other forms of treatment.
Initial trials with allergen-non-specific anti-IgE antibodies to deplete the patient of allergen-specific IgE antibodies have shown early promise (Boulet, et al. 1997; 155:1835-1840; Fahy, et al. American J Respir. Crit. Care Med. 1997; 155:1828-1834; Demoly P. and Bousquet J. American J Resp. Crit. Care Med. 1997; 155:1825-1827). On the other hand, trials utilizing immunogenic peptides (representing T cell epitopes) have been disappointing (Norman, et al. J. Aller. Clin. Immunol. 1997; 99:S127). Another form of allergen-specific immunotherapy which utilizes injection of plasmid DNA (Raz et al. Proc. Nat. Acad. Sci. USA 1994; 91:9519-9523; Hz et al. Int. Immunol. 1996; 8:1405-1411) remains unproven.
There remains a need for a safe and efficacious therapy for allergies, especially those where traditional immunotherapy is ill advised due to risk to the patient or lack of efficacy. There is also a need for alternatives to therapies, for example, by creating foods, materials or substances that do not include the allergens that are most problematic, or which contain modified allergens which do not elicit the same reaction. While the technology to make genetically engineered plants and animals is at this point well established, useful modifications would require understanding how allergens can be modified so that they retain the essential functions for the plants' and animals' nutritional value, taste characteristics, etc., but no longer elicit as severe an allergic response.
It is therefore an object of the present invention to provide a method for decreasing the allergenicity of allergens either by modifying the allergen itself or by producing a compound that would mask the epitope and thus prevent binding of IgE.
It is a further object of the present invention to provide allergens that elicit fewer IgE mediated responses.
It is still another object of the present invention to provide a method to make genetically engineered plants and animals that elicit less of an allergic response than the naturally occurring organisms.